Abstract
BackgroundThe development of thrombocytopenia in sepsis is a poor prognostic indicator associated with a significantly increased mortality risk. Mechanisms underlying this phenomenon remain to be clearly elucidated. Matrix metalloproteinases (MMPs) are enzymes that regulate the turnover of the extra-cellular matrix. MMP-2 is recognised as a platelet agonist with MMP-9 proposed as an inhibitor of platelet activation. The existence of MMP-9 in platelets is a subject of debate. There is limited evidence thus far to suggest that toll-like receptor 4 (TLR-4) and platelet-leukocyte aggregate (PLA) formation may be implicated in the development of sepsis-associated thrombocytopenia.ObjectivesTo investigate whether MMP -2/-9, toll-like receptor 4 (TLR-4) or platelet-leukocyte aggregate (PLA) formation are implicated in a decline in platelet numbers during septic shock.MethodsThis was an observational study which recruited healthy controls, non-thrombocytopenic septic donors and thrombocytopenic septic donors. MMP-2, MMP-9 and TLR-4 platelet surface expression as well as PLA formation was examined using flow cytometry. In addition MMP-2 and MMP-9 were examined by gelatin zymography and enzyme-linked immunosorbent assay (ELISA) using a 3 compartment model (plasma, intraplatelet and platelet membrane).ResultsThere was no difference found in MMP-2, MMP-9 or TLR-4 levels between non-thrombocytopenic and thrombocytopenic septic donors. PLA formation was increased in thrombocytopenic patients. MMP-9 was detected in platelets using flow cytometry, gelatin zymography and ELISA techniques.ConclusionsPlatelet consumption into PLAs may account for the development of thrombocytopenia in septic shock. MMP-9 is found in platelets and it is upregulated during septic shock.
Highlights
Severe sepsis is often associated with a decrease in platelet numbers
There was no difference found in Matrix metalloproteinases (MMPs)-2, MMP-9 or toll-like receptor 4 (TLR-4) levels between non-thrombocytopenic and thrombocytopenic septic donors
MMP-9 was detected in platelets using flow cytometry, gelatin zymography and enzyme-linked immunosorbent assay (ELISA) techniques
Summary
Severe sepsis is often associated with a decrease in platelet numbers. With platelet counts below 150,000/μl widely accepted as thrombocytopenia [1], reported rates of sepsis-associated thrombocytopenia in the literature range from 14.5% to 70.6% [2, 3]. MMP-2 is recognised as a mediator of platelet activation [14, 15]. Another gelatinase, MMP-9, has been proposed as an inhibitor of platelet aggregation [16]; whether MMP-9 can be found in platelets remains a matter of debate [17,18,19]. The development of thrombocytopenia in sepsis is a poor prognostic indicator associated with a significantly increased mortality risk. Mechanisms underlying this phenomenon remain to be clearly elucidated. There is limited evidence far to suggest that toll-like receptor 4 (TLR-4) and platelet-leukocyte aggregate (PLA) formation may be implicated in the development of sepsis-associated thrombocytopenia
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